Penn Researchers Discover A Molecular
Pathway That Leads to Recurrence of Breast Cancer

Study May Help Find Ways to Prevent
Recurrence

(Philadelphia, PA) - Using a recently developed
mouse model of breast cancer, a team from the University
of Pennsylvania School of Medicine has shown that Snail,
a molecule normally important in embryonic development, can promote
breast cancer recurrence. They also found that high Snail expression
predicts more rapid tumor recurrence in women who have been treated
for breast cancer. These observations suggest that Snail may represent
a target for cancer therapy.

Among women, breast cancer is the most common cancer worldwide
and is the leading cause of cancer mortality. Of the more than 5
million women currently living with a diagnosis of breast cancer,
recurrence represents the most common cause of death from this disease.
Remarkably, recurrences can appear up to 20 years following surgery,
although most occur within the first two years. "Up to 40 percent
of women thought to be cancer free following surgery, radiation,
and chemotherapy still have tumor cells in their bodies in a dormant
state. As such, approaches to prevent cancer recurrence in these
women would be broadly applicable," says senior author Lewis
A. Chodosh, MD, PhD, Vice Chair of the Department of Cancer
Biology and Director of Cancer Genetics at the Abramson
Family Cancer Research Institute at Penn. The researchers
published their findings in the September 2005 issue of Cancer
Cell.

"To this point there are extraordinarily few targets that
have been causally implicated in breast cancer recurrence. Consequently,
there are few treatments available to offer women who are at risk
for recurrence once they have received standard treatments,"
says Chodosh.

The Penn team of researchers induced breast cancer in the genetically
engineered mice by giving doxycycline to turn on the oncogene HER-2/neu.
This oncogene is commonly amplified in human breast cancers and
is associated with aggressive disease and poor clinical outcome.
The researchers then induced these tumors to regress by turning
off the HER2/neu oncogene in fully formed tumors. This mimics important
aspects of molecularly targeted therapies and leads to the dramatic
regression of tumors to a clinically undetectable state. Nevertheless,
residual tumor cells lie in a dormant state and later grow out after
a month to a year in the mice.

Using
microarrays, Chodosh's team compared recurrent tumors with the original
tumors from which they arose. They found that a variety of genes
were turned on in recurrent tumors that were not on in the original
tumors, including the transcriptional regulatory protein, Snail,
which was induced ten-fold. The Penn team also identified changes
in the microscopic appearance of the cells in recurrent tumors,
which had transformed from a cuboidal, epithelial shape to a spindle,
fibroblastic shape - a change associated with more aggressive tumors
in humans.

Snail was first identified in fruit flies and later in mice based
on its essential role in embryogenesis during a developmental transition
in which normal cells undergo a similar change in shape. "Snail
controls a complex set of cellular functions that cancer cells appropriate
by turning on this master regulatory gene," explains Chodosh.

To prove a cause-and-effect, the researchers added Snail back to
the original tumor cells in mice and showed that Snail increased
the rate of recurrence.

But could Snail expression play a similar role in women with breast
cancer? When the Penn team delved into public databases of breast
cancer tissue data, separating cases into those with high levels
of Snail and those with low levels of Snail, they found that women
whose original breast cancers expressed high levels of Snail were
twice as likely to experience a recurrence within five years following
surgery compared to women whose cancers expressed low levels of
Snail.

The magnitude of risk associated with high Snail expression is
comparable to standard prognostic factors such as estrogen-receptor
status, HER-2/Neu amplification, tumor size and grade, and lymph
node status and - after correcting for the effects of these factors
- Snail expression was shown to predict a woman’s risk of
recurrence independent of these factors.

Currently, Chodosh and colleagues are exploring the precise molecular
mechanism by which Snail triggers breast cancer recurrence, as well
as ways of targeting Snail's signaling pathways as a possible therapeutic
approach to prevent recurrence.

This research was funded by the National Cancer Institute and the
US Army Breast Cancer Research Program. Co-authors are Susan Moody,
Denise Perez, Tien-chi Pan, Christopher J. Sterner, and Kathleen
L. Notorfrancesco, all from Penn, as well as Robert D. Cardiff from
the University of California, Davis.

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